Identification of a CD4 Domain Required for Interleukin-16 Binding and Lymphocyte Activation*

Liu, Yu; Cruikshank, William W.; O'Loughlin, Terence; O’Reilly, Philip; Center, David M.; Kornfeld, Hardy

doi:10.1074/jbc.274.33.23387

Cited by 60 publications

(52 citation statements)

References 38 publications

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“…In addition, CD4 oligomerization has been reported to be critical for an efficient interaction of CD4 with other ligands, such as gp160 or IL-16 (6 -10, 41). Moreover, residues within the dimerization site have been shown to be essential for both IL-16 binding and lymphocyte activation (41). Direct evidence for the presence of oligomeric forms of human CD4 in lymphoid and monocytoid cells was provided by Cunningham and colleagues (17).…”

Section: Discussionmentioning

confidence: 93%

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

Moldovan

Yachou

Lévesque³

et al. 2002

The Journal of Immunology

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The CD4 molecule plays a key role in the development and activation of helper T cells. Dimerization and oligomerization is often a necessary step in the function of several cell surface receptors. Herein, we provide direct biochemical evidence confirming the presence of CD4 as dimers in transfected cells from hemopoetic and fibroblastic origin as well as in primary T cells. Such dimers are also observed with murine CD4 confirming selective pressure during evolution to maintain such a structure. Using a series of point mutations, we have precisely mapped the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. These residues are highly conserved and their mutation results in interference with dimer formation. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. These data strongly suggest that CD4 dimerization is necessary for helper T cell function.

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Section: Discussionmentioning

confidence: 93%

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

Moldovan

Yachou

Lévesque³

et al. 2002

The Journal of Immunology

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“…It is possible that IL-16 binds in a manner similar to that of gp120 whereby association with CD4 structurally alters CCR5, allowing for direct binding to CCR5. Alternatively, the presence of CCR5 associated with CD4 may structurally alter CD4, thus allowing for stronger interaction of IL-16 with the D4 domain of CD4 (6). The ability of CCR5 to increase IL-16 binding may also result in signal transduction mediated by CCR5.…”

Section: Il-16-induced Migration Of and Binding To Ccr5 ϫ/ϫ Cellsmentioning

confidence: 99%

“…Subsequent studies identified that IL-16 was a chemoattractant for a number of other immune cells such as monocytes, eosinophils, and dendritic cells (3)(4)(5). IL-16 has been characterized as a natural ligand for CD4 (6,7), given that direct association with the D4 domain of CD4 results in activation of p56 lck and phosphatidylinositol 3-kinase (PI 3 kinase) 3 (8). Recent studies have suggested that IL-16 may signal through an alternative receptor in cells from the monocytoid lineage, as CD4 null epidermal dendritic cells and monocytes obtained from CD4 null mice are responsive to IL-16 (9,10).…”

mentioning

confidence: 99%

Cutting Edge: IL-16/CD4 Preferentially Induces Th1 Cell Migration: Requirement of CCR5

Lynch

Heijens

Horst

et al. 2003

The Journal of Immunology

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103

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IL-16 binds to CD4 and induces a migratory response in CD4+ T cells. Although it has been assumed that CD4 is the sole receptor and that IL-16 induces a comparable migratory response in all CD4+ T cells, this has not been investigated. In this study, we determined that IL-16 preferentially induces a migratory response in Th1 cells. Because chemokine receptor CCR5 is expressed predominantly in Th1 cells and is physically associated with CD4, we investigated whether IL-16/CD4 stimulation was enhanced in the presence of CCR5. Using T cells from CCR5null mice, we determined that IL-16-induced migration was significantly greater in the presence of CCR5. The presence of CCR5 significantly increased IL-16 binding vs CD4 alone; however, IL-16 could not bind to CCR5 alone. Because CD4+CCR5+ cells are prevalent at sites of inflammation, this intimate functional relationship likely plays a pivotal role for the recruitment and activation of Th1 cells.

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“…[15][16][17][18] Expression of IL-16 by the bronchial epithelium in patients with asthma, by the dermis and epidermis in patients with atopic dermatitis, and by synovial fibroblasts in patients with rheumatoid arthritis was found to correlate with CD4 ϩ cell influx. 15,[17][18][19] Furthermore, recombinant IL-16 induced chemotaxis of CD4 ϩ T cells in vitro through interaction with CD4, 13,14 and HIV-1 gp120 binding to CD4 increased CD4 T-cell activation and directed cell migration in vitro. 20,21 In the current study, we expanded on our previous findings and determined that the level of CD4 cell-surface expression on CD8 ϩ T cells is directly proportional to the level of costimulation with T-cell receptor and CD28.…”

Section: Introductionmentioning

confidence: 99%

Activation of CD8 T cells induces expression of CD4, which functions as a chemotactic receptor

Kitchen

LaForge

Patel

et al. 2002

Blood

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IntroductionThe CD4 protein has many different functions in the development and activity of a T cell. CD4 has an important role in T-helper (Th)-cell development and response to antigen in the context of major histocompatibility complex class II (MHC II). It also serves as an adhesion molecule and a chemotactic receptor, and it has a role in cellular activation. CD4, a 58-kd transmembrane glycoprotein, is a member of the immunoglobulin family of receptors. 1 The extracellular 370-amino acid portion of CD4 is folded into 4 different domains, which are designated D1 to D4. 1 These domains are involved in a variety of interactions with other proteins, such as the T-cell receptor, MHC II,, and human immunodeficiency virus (HIV) gp120. Engagement of CD4 plays an important role in the initiation of events that lead to activation of Th cells or recruitment of those cells to sites of inflammation. The cytoplasmic tail of the CD4 protein was shown to associate noncovalently with Lck, a Src-family protein tyrosine kinase. 2,3 Cross-linking of CD4 with monoclonal antibodies (mAbs) or stimulation of CD4 by IL-16 results in Lck tyrosine phosphorylation and subsequent tyrosine phosphorylation of other cellular proteins. [4][5][6] These tyrosine phosphorylation events lead to modulation of cellular activation and functional responses. 7 CD4 expression is tightly regulated during the T-cell development process, and this control has an important role in T-cell maturation and function. The coordinate cell-surface expression of CD4 and CD8 and the subsequent down-regulation of either CD4 or CD8 are definitive markers of T-cell ontogeny. Furthermore, expression of one of these molecules on mature T cells is indicative of successful selection and commitment of these cells to either the Th or T-cytotoxic lineage. 8 However, previous ideas on the terminal differentiation of a cell into either a CD4 ϩ CD8 Ϫ Th cell or a CD4 Ϫ CD8 ϩ T-cytotoxic cell have been questioned. Several studies, including one of ours, found that activation of mature CD4 Ϫ CD8 ϩ (CD8 single-positive [SP]) T cells by costimulation 9,10 or superantigen stimulation 11 results in expression of CD4, which renders these cells susceptible to infection by HIV-1. [9][10][11] We previously found that CD45RA ϩ CD8 SP cells respond to costimulation with greater expression of CD4 than do CD45RO ϩ CD8 SP cells. 10 Thus, expression of CD4 can be modulated on T cells at more mature stages of development than was previously thought, suggesting that CD4 may be involved in mature CD8 T-cell function.The CD4 molecule was previously shown to function as a chemotactic receptor for both IL-16 and the viral surface glycoprotein HIV gp120 on CD4 ϩ Th cells. IL-16 specifically binds the D4 region, and gp120 binds the D1 region of CD4. 12,13 IL-16 is a 14-kd molecule that forms homotetramers, which are required for biologic activity. 14 This cytokine is produced by a variety of cells, including CD8 and CD4 T cells, eosinophils, mast cells, bronchial epithelial cells, synovial fibroblasts,...

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Identification of a CD4 Domain Required for Interleukin-16 Binding and Lymphocyte Activation*

Cited by 60 publications

References 38 publications

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

Cutting Edge: IL-16/CD4 Preferentially Induces Th1 Cell Migration: Requirement of CCR5

Activation of CD8 T cells induces expression of CD4, which functions as a chemotactic receptor

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